Evaluation of linkage disequilibrium between chromosome 22q11 single nucleotide polymorphisms in a large outbred population.

To assess the utility of linkage disequilibrium (LD) as a tool for fine-mapping disease genes in non-isolated populations, we have assessed the linkage disequilibrium strength among a series of single nucleotide polymorphisms (SNPs) in an approximate 1 Mb region of human chromosome 22q11. Nineteen random SNPs were discovered and tested across this region with an average spacing of 57 kb (range = 1.4–289 kb). These 19 SNPs were genotyped in a population consisting of 444 unrelated pedigrees that were largely collected in the U.S. and U.K. Haplotypes for all pedigrees were derived from pedigree data and over 1,400 haplotypes from unrelated individuals were evaluated for linkage disequilibrium between marker alleles. In addition, linkage disequilibrium between marker alleles was also evaluated using estimated haplotypes without genealogical information (i.e., without parental genotype information). Every marker pair combination was tested for a total of 171 tests and 2 × 2 contingency tables were constructed to measure LD strength. In general the haplotypes derived from pedigree data provided a more conservative estimate of LD strength. Using genealogical information for estimates of D′, 59% (10/17) of marker pairs less than 50 kb apart had D′ values > 0.30. Finally, we observed a 60 kb region with non-significant LD, which could reflect increased recombination in this region. © 2002 Wiley-Liss, Inc.